Residual Immunity from Smallpox Vaccination and Possible Protection from Mpox, China

Among persons born in China before 1980 and tested for vaccinia virus Tiantan strain (VVT), 28.7% (137/478) had neutralizing antibodies, 71.4% (25/35) had memory B-cell responses, and 65.7% (23/35) had memory T-cell responses to VVT. Because of cross-immunity between the viruses, these findings can help guide mpox vaccination strategies in China.

smallpox vaccination provided ≈85% protection against mpox (3).Because the World Health Organization declared that smallpox had been eradicated and routine use of vaccinia vaccine was terminated in most countries by 1980-1981, most persons born after 1980 do not have vaccinia virus-elicited immunity.Vaccinia-derived protection wanes in the vaccinated population over time, which may lead to an increase in susceptibility to monkeypox virus (MPXV) infection because of cross-immunity between the 2 viruses.
After the first mpox case imported from Europe to mainland China on September 14, 2022 (4), investigation of the level of residual VTT-specific immunity in the population of China became pressing, as researchers assessed susceptibility to mpox and guided development of appropriate protective strategies.Different patterns of residual immunity against vaccinia suggest different strategies in responding to mpox transmission.However, levels of residual immunity to poxviruses in the population in China are not well assessed.We measured VTTspecific humoral and cellular immune responses in a diverse population born during 1930-2008 in China.

DISPATCHES
1 These first authors contributed equally to this article. 2These senior authors contributed equally to this article.We tested serum samples from all participants to determine IgG titers against VTT by using ELISA.We performed a Gaussia luciferase-based vaccinia neutralization assay to determine the presence of neutralizing antibodies (NAbs).We performed memory Bcell and memory T-cell enzyme-linked immunospot (ELISpot) assays (Charles River Laboratories, https:// www.criver.com)by using cryopreserved peripheral blood mononuclear cells (PBMCs).Because of insufficient PBMC samples, we evaluated memory B-and T-cell responses in a subgroup of the enrolled participants (Appendix Figure 1 We examined distribution of NAb levels in relation to year of birth (Table 2; Figure 1 We observed a significant correlation between NAb and IgG titers in persons born before 1990 (Spearman r = 0.54; p<0.0001) (Appendix Figure 2, panel C).
We measured VTT-specific memory B-cell responses in 45 participants whose PBMCs were isolated successfully (Appendix Figure 3).As a control, we tested for influenza virus and Epstein Barr virus-specific memory T-cell responses, which we detected in persons born during 1940-2008 (Appendix Figure 7, panel A).Among the 35 persons born before 1980 and found to be positive for specific cellular immune responses, 28 (80%) had no detectable NAb (<1/4).However, 67.9% (19/28) persons showed IFN-γ responses in the ELISpot assay (Appendix Figure 7, panel B).

Conclusions
We evaluated residual VTT immunity in the population of China across >5 birth decades.Our and other studies suggest that antibody responses against vaccinia virus after vaccination can be long-lived (5)(6)(7).We observed a low prevalence (28.7% [137/478]) of NAb against VTT in persons born before 1980, which is consistent with a previous study in the population of China (8).Our data demonstrate that 71.4% of the 35 tested participants born before 1980 had VTT-specific memory B-cell responses.Those memory B-cells can still rapidly differentiate into plasma cells and produce protective antibodies upon reinfection (9).Smallpox vaccine-induced antibodies may protect against MPXV (10).Approximately 65.7% of the 35 participants born before 1980 that we tested had VTT-specific T-cell responses, which is consistent with previous reports that T-cell responses against vaccinia virus were maintained up to 51-75 years postimmunization and had a half-life of 8-15 years (5,7).
One limitation of our study is that it is a crosssectional study.In addition, no information regarding smallpox vaccination or smallpox infection was available for the persons enrolled.Moreover, a small number of samples were tested for T-and B-memory cell responses.
In summary, we evaluated residual immune responses to VTT in the population of China and found that >65% of 35 tested persons born before 1980 showed memory B-and T-cell responses.However, the prevalence and NAb titers against VTT were low in this population.To protect the population from infection by MPXV and any other related pathogenic orthopoxviruses, safe and effective vaccines will be needed for all age groups.

Table 1 .
Characteristics of 1,070 participants in a cross-sectional cohort study to determine IgG titers against vaccinia virus Tiantan strain, China* Participants lived in Beijing, Shanxi Province, Heilongjiang Province, Hubei Province, or Shenzhen.. *